Taken together, using an mRNA expression‐based BCSC signature, we demonstrate the critical role of polyamine anabolism in the regulation of chemotherapy‐induced BCSC enrichment, and provide compelling evidence that targeting HIF‐1‐controlled polyamine anabolism with novel inhibitor britannin efficiently eradicates BCSCs and may improve treatment outcome in breast cancer patients. This evidence concerns the gene HIF1A and breast cancer.